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Review Molecular Imaging and Radionuclide Therapy 2011;20(3): 75-93 DOI: 10.4274/MIRT.33

An Overview on Coronary Heart Disease (A Comparative Evaluation of Turkey and Europe) and Cost-effectiveness of Diagnostic Strategies Koroner Kalp Hastalığına Genel Bakış (Türkiye ile Avrupa Arasında Bir Karşılaştırma) ve Tanısal Stratejilerin Maliyet Etkinliği Cengiz Taşçı, Nihat Özçelik Gama Tıp Merkezi, Nükleer Tıp Bölümü, Gaziantep, Turkey

Abstract Objective: Coronary heart disease (CHD) is the leading cause of death for men and women in Turkey as it is in Europe and US. The prevalence of the disease is 3.8% in Turkey and 200,000 patients are added to the pool of CHD annually. Because of genetic predisposition and high proportions of physical inactivity, smoking habit, and obesity, CHD is encountered in earlier ages in our country. So, the economic burden of the disease is expected to be relatively high, but the amount of health expenditure is not always parallel to the prevalence of a disease in the community. This article was written to overview CHD statistics to make a comparison between Turkey and some European countries and to investigate the value of myocardial perfusion scan (MPS) as a gatekeeper in diagnosing CHD before invasive coronary angiography (ICA). The consequences were evaluated for Turkey. In diagnosis; noninvasive testing gains importance in connection with the new approaches in treatment strategies, because a direct ICA strategy results in higher rates of revascularization without improvement in clinical outcomes. A “gatekeeper” is needed to select the patients who are not required to undergo angiography. MPS with its proved power in diagnosis and predicting prognosis, provides a cost-effective solution, and is accepted in some extensive analyses as a “gatekeeper” particularly in intermediate and high risk patients and in patients with known CHD. In conclusion, MPS may provide an optimal solution better than the ongoing situation in Turkey as well, when it is approved as a “gatekeeper in an algorithm before ICA. (MIRT 2011;20:75-93) Key words: Coronary heart disease, cardiac noninvasive testing, cost-effectiveness, myocardial perfusion scan

Özet Amaç: Koroner kalp hastalığı (KKH), Avrupa’da ve Amerika’da olduğu gibi Türkiye’de de kadın ve erkekler arasında önde gelen ölüm sebebidir. Ülkemizde hastalığın prevalansı %3.8’dir ve her yıl KKH havuzuna ortalama 200 000 hasta eklenmektedir. Türkiye’de daha genç yaşlarda iskemik kalp hastalığına rastlanmaktadır. Türklerin genetik yatkınlığının yanı sıra, toplumumuzda günlük egzersiz alışkanlığının az olması, sigara alışkanlığı ve obezitenin yüksek oranda bulunması gibi nedenler, KKH’nın erken yaşlarda görülmesini etkilemektedir. Hastalığa ayrılan sağlık harcamasının da görece yüksek olması beklenebilir, ancak bir hastalık için yapılan toplam ya da kişi başı sağlık harcaması her zaman o hastalığın toplumdaki prevalansı ile paralel değildir. Bu çalışmada, Türkiye ile bazı Avrupa ülkeleri arasında KKH istatistikleri açısından bir karşılaştırma yapıldı ve miyokard perfüzyon sintigrafisi (MPS)’‘nin koroner anjiyografi öncesinde bir eleyici test olarak kullanılmasının klinik ve ekonomik sonuçları incelendi. Bu sonuçlar ülkemiz açısından da değerlendirildi. Tedavi stratejilerindeki yeni yaklaşımlara paralel olarak revaskülarizasyondan yarar görebilecek yüksek riskli hastaları seçmek için girişimsel olmayan testler önem kazanmıştır. Öte yandan, tanı için hastalara doğrudan anjiyografi yapılmasının, klinik sonuçları değiştirmediği halde yüksek oranlarda revaskülarizasyona yol açtığı görüldüğünden, hasta seçiminde eleyici bir öncü teste ihtiyaç ortaya çıkmıştır. Klinik sonuçları en iyi öngörebilen ekonomik bir test olması dolayısıyla, MPS literatürde, özellikle orta ve yüksek riskli hastalar ile bilinen KKH olanlarda böyle bir rol için önerilmektedir. Anjiyografi öncesinde bir eleyici test olarak kabul edilmesi halinde, MPS Türkiye’de de klinik ve ekonomik sonuçlar açısından mevcut duruma göre daha iyi bir çözüm sağlayabilir. (MIRT 2011;20:75-93) Anahtar kelimeler: Koroner kalp hastalığı, tanısal testler, maliyet etkinlik analizi, miyokard perfüzyon sintigrafisi

Address for Correspondence: Cengiz Taşçı MD, Gama Tıp Merkezi, Nükleer Tıp, Gaziantep, Turkey Phone: +90 342 221 10 07 E-mail: [email protected] Received: 14.06.2011 Accepted: 14.10.2011 Molecular Imaging and Radionuclide Therapy, published by Galenos Publishing.

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Taşçı et al. An Overview on Coronary Heart Disease

(15). The total prevalence is 3.8% (4.1% in males and 3.5% in females). There were approximately 1 million patients in 1990 and the number reached 3.1 million up to 2008. 390 000 new coronary artery events and 190 000 deaths are encountered each year. This means that 200 000 patients are added to the pool of CHD yearly (15) (Figure 4). Coronary mortality rate in 45-74 year-old individuals is reported as 0.57% (0.76% in males and 0.38% in females) between 1990-2008 and a decreasing trend in rising rates was recorded between 2000-2008 (15,16). In an European analysis in 2000 that did not include Russia and Ukraine, the annual mortality from CHD in 45-74 years of age was found highest in Turkish women and second highest in Turkish men after Latvians (Figure 3). Coronary mortality rates are approximately 3 times more in Turkish men and 5 times more in Turkish women than those in Western Europe (15,16,17). CHD is encountered in earlier ages in Turkey. The prevalence of the disease is about 6% in 45-54 year-old individuals, which is considered to be relatively high for this age population (15). Every ten years of aging increases the risk of CHD 1.8 fold in men and 1.9 fold in women (18). Actually, Turkey is a unique country with its young population among European countries. Population over 65 years old (65+) was 5.8% in 2008, while the average of European countries was 15.3% (Table 2). Since the age is the most important independent risk factor (18) and CHD is seen generally in elder people over 65 years old (65+), it is surprising that CHD is the first cause of death in Turkey as it is in the developed countries with aged populations. 2009 statistics by Turkish Ministry of Health indicated that population aged 65+ was 4.3% in 1990, 5.7% in 2000, 6.7% in 2008 (not age-standardized), and 7.0% in 2009 (19). Very far off from the rates in Europe but the statistics indicate an increase in elder people in Turkish population probably because the average life and life expectancy is getting longer due to advanced treatment options. On the other hand, CHD is a complex disorder resulting from many risk factors. Genetic predisposition for atherosclerosis is a substantial risk for developing CHD especially at early ages. Turkish adults –both men and womenhave the lowest levels of total cholesterol (TC) and HDL-C among the citizens of all European countries (Table 3). Several comparative studies including Turks living in Germany and US confirm that HDL-C levels in Turks are among the lowest in the

Introduction The Prevalence and the Incidence of CHD in Europe and Turkey Coronary heart disease (CHD) is an important health problem in Turkey as it is in Europe and US, because it is the leading cause of death for men and women, and it causes substantial disability and loss of productivity (1,2,3,4,5). The World Health Organization (WHO) assessments about 15 leading causes of death worldwide had indicated that ischemic heart disease would move from number five position in 1990 to number one position in 2020 (2,4). This estimation was first made in 1996, but the recent studies evaluating the global burden of disease (last updated for 2004) revealed that this had become already a fact particularly in the developed and developing countries (6,7,8). According to the WHO projections, the number of deaths due to CHD will increase in the future all over the world. This trend is expected to continue for the next 30 years (8) (Figure 1). European cardiovascular disease (CVD) statistics indicate that CHD by itself is the most common cause of death in Europe and in European Union (EU) (Figure 2). 1.92 million deaths (21% of men and 22% of women deaths) from CHD in Europe and 741,000 deaths (16% of men and 15% of women deaths) in EU are accounted each year. There is a marked west-east gradient in the age standardized cardiovascular mortality rates. Death rate from CHD is relatively low and decreases steadily in Northern, Southern and Western Europe, while it is high and increases in Central and Eastern Europe including Turkey. Cardiovascular mortality rates for women are lower than those for men in all European countries (3,9,10,11,12) (Figure 3). “Turkey Burden of Disease Study, 2004” by Refik Saydam Hygiene Center (RSHC) on behalf of the Ministry of Health and TEKHARF Studies by A. Onat et al. also confirm that ischemic heart disease is the leading cause of death in Turkey (1,13,14,15) (Table 1). CHD is responsible for 20.7% of male, and 22.9% of female deaths (21.7% of all) (1). These numbers are very close to the average of Europe, but higher than the average of EU (3,9,10,11,12,15). As it is in the other Eastern European Countries, CHD rates increase each year in Turkey (13,14,15). The prevalence of the disease in individuals over 50 years old was found to be increased by 80% in 20072008 TEKHARF study, when compared to the study in 1990

100%

30

80%

25

Deaths (millions)

20 15 10 5

Suicide, homicide and war Other unintentional injuries Road traffic accidents Other noncommunicable diseases Cancers Cardiovascular diseases Meternal, perinatal and nutritional conditions Other infectious diseases HIV/AIDS, TB and malaria

60%

40% 20% 0% 0

0

2004 20152030 2004 20152030 2004 20152030 High income Middle income Low income Data from WHO report updated for he year 2004 (8), with permission

10

20

Cardiovascular diseases Cancer

Figure 1. Deaths by cause for high-, middle and low-income countries in the future

30

40

50 60 70 AGE Respiratory diseases External causes of injury

80

≥80

Total

Digestive disease Other

Figure 2. Major causes of death by age in Europe from Euro Heart survey 2006 (9)

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Taşçı et al. An Overview on Coronary Heart Disease

world. Therefore, the ratio of TC/HDL-C, the best independent lipid predictor of CHD, is very high in Turkish adults. Low levels of TC, LDL-C and HDL-C are associated with high levels of hepatic lipase, fasting triglycerides and high levels of apolipoprotein-B (20,21,22,23,24). This lipid profile pointing out a genetic disorder constitutes a significant early predisposition to CHD. Positively, the percentage of total energy available from fat is relatively low in Turkish people and the average amount of fruit and vegetable intake per person is the second greatest in Turkey after Greece among all European countries (Table 4). There are some regional differences in diet habits ranging from the Aegean coast diet rich in olive oil to the inland 24

FRANCE

110

39

SPAIN

151

65

GRECEE

231

80

GERMANY

Females

244

104

ENGLAND

Males

307 92

FINLAND

per 100.000 372

157

BULGARIA

404

189

UTHUANIA

598 260

ESTONIA

713

242

LATVIA

781 384

TURKEY 0

Anatolian diet rich in meat and pastry. Alcohol consumption is distinctively low in our country, so that moderate alcohol consumption reduces the risk of CHD while high level of intake increases (Table 4). But, physical inactivity common in both genders, smoking habit especially in men and obesity highest in Turkish women in Europe result in HT, diabetes, metabolic syndrome and finally a high prevalence of CHD (Table 3). All these factors probably are the reasons of unanticipated fact that Turkish adults have the pattern of death causes similar to the population of developed countries (20). In paralel to these predispositions, TEKHARF studies indicate that Framingham risk scoring when applied to the Turkish adults underestimates the risks in reality, because the absolute coronary event risk is much higher in Turkey (18). Economic Burden of CHD CHD is estimated to cost the EU economy €49 billion a year, about 2.6% of total healthcare expenditure. CHD healthcare cost per capita is about €50 in EU, when purchasing power parity (PPP) is used (25) (Table 5). Of the total cost of CHD in EU, about 48% is due to direct health care costs, 34% to productivity losses and 18% to the informal care costs. Of the total direct healthcare costs, about 62% is due to inpatient care, 23% to medications, and remaining 16% to primary care, outpatient care and accident & emergency (25) (Figure 5,6). Unfortunately, there is no data available about diseasespecific costs in Turkey, but some projections may be done for the economic burden of CHD using data from EU. According to an analysis of Europe in 2002 (12), Estonia, Latvia, Lithuania, Hungary, Romania and Bulgaria seem to be the closest countries to Turkey in terms of age-standardized disability-adjusted life years (DALYs) rate for CHD (Table 2, Figure 7,8). DALYs for a specific disease are calculated as the sum of the years of life lost due to premature mortality (YLL) and the years lost due to disability (YLD) (6). One DALY is defined as the loss of one year of equivalent full health. So, DALYs rate represents the consequences of morbidity and

100

200

764

300 400 500 600

700 800

900

Figure 3. Age standardized mortality rates in 45-74 years old people with CHD in Europe, 2000 (15-17). Modified from Ref 15

CHD Pool 3.1 million people +200.000/each year

100.000

300.000

90.000 Death from CHD - 190.000/ year

New Case CHD +390.000 /year

Table 1. Ten Leading Causes of Death (Turkey, 2004) Causes of Death

Figure 4. Patient population, new cases and death from CHD in Turkish adults (15). With permission of A. Onat

1. Ischemic Heart Disease 2. Cerebrovascular Disease 3. COPD 4. Perinatal Causes 5. Lower Respiratory Infections 6. Hypertensive Heart Disease 7. Trachea, bronchus and lung cancers 8. Diabetes Mellitus 9. Road Traffic Accidents 10. Inflammatory Heart Diseases

Direct Health Care €23 billion

34% 51% 15%

Informal Care €7 billion

Productivity losses €15 billion

Formed with the data from Ref. 25

Number of Deaths

Percent Total

93.260 64.780 25.104 24.756 18.225 12.805 11.586

21.7 15.0 5.8 5.8 4.2 3.0 2.7

9.548 8.395 7.992

2.2 2.0 1.9

Data from TURKEY BURDEN OF DISEASE STUDY 2004 (1). With permission of RSHC

Figure 5. Economic burden of CHD in EU, in 2003 (Overall cost is € 49 bilion a year)

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Taşçı et al. An Overview on Coronary Heart Disease

uncorrelated to the other parameters (Table 2). Turkey seems to be in the same class with these six Eastern European countries in terms of GNIpc, total health expenditure per capita and age standardized DALYs rate for CHD. So, the average cost per capita on CHD may be expected to be similar in this group of countries and estimated about €20 (PPP€) as the average of 4 of 7 countries calculated from the same study for the year 2003. (Table 5). This may roughly represent the average per person in Turkey, too.

mortality from a disease together. Mortality rates from CHD are not always parallel to the DALYs rates, that’s why not mortality rates alone but DALY’s rates for CHD may be expected to have correlation with total or per capita health expenditure on CHD. As it is expected, J. Leal et al., found no direct correlation between CVD-related health expenditure and mortality rates or life expectancy (25). Anyway, coronary mortality rates are close in these seven low-income countries and the rates are higher than those in high-income countries in Europe (Table 2, Figure 8). Life expectancy, the second lowest in Turkish population after Ukrainians, is also similar in these seven countries. In the same study by J. Leal et al., a strong positive correlation was indicated between CVDrelated health expenditure and national income. The Gross National Income per capita (GNIpc) and the total health expenditure per capita in these seven countries are close, too (Table 5, Figure 9). Hospital discharge from CHD is found

Diagnostic Strategies in Stable CHD in Connection with the Treatment Strategies Understanding the Biology of CHD CHD is a general term for atherosclerosis in the coronary vessels and it appears in various stages. Fatty material and other substances form a plaque on the walls of the vessels.

Table 2. CHD related statistics in some European countries Life expectancy at birth, 2008 (years)

Life expectancy at age 65, 2008 (years)

% of population Death rates aged 65+ from CHD (45-74 y), 2008 (%) 2000 per 100,000

DALYs rate Hospital discharges of CHD (45-74 y) from CHD, 2008 2005 per 100,000 per 100,000

Germany

80.0*

19.2*

20.2

157

574

916

UK

80.0

19.2

16.2

202

657

444

Finland

80.0

19.7

16.7

222

687

865*

France

81.4

21.0

16.6

65

259

497

Spain

81.5

20.4

16.6

92

368

302

Greece

80.1

19.0

18.7

144

620

970*

Estonia

74.3

16.9

17.2

446

1.449

999

Hungary

74.2

16.4

16.3

343

1.137

808

Latvia

72.5

16.0

17.3

461

1.606

1.472

Lithuania

72.0

16.3

15.9

357

1.444

1.297

Romania

73.5

15.8

14.9

322

1.176

367

Turkey

71.9

**

5.8

570 *

1.332

524

Bulgaria

73.4

15.3

17.4

271

1.344

1.017

Data from European CVD Statistics,

804 Data from Who/Europe database (26).

EU European Region 75.5 Source Data from Who/Europe database (26). * 2006

17.4 Data from Who/Europe database (26). * 2006 **No data

15.3 220** Data from Data from the Who/Europe study, 2008 database (26). J. Müller-Nordhorn (17). Age-standardized to WHO population

* 1990-2008. Data from the study by A. Onat et al. (16). ** 2000, Data from Who/Europe database (26).

78

2008 by British Heart Foundation (12). DALYs: Disability-adjusted life years.

* 2006

Taşçı et al. An Overview on Coronary Heart Disease

This chronic process narrows the coronary arteries which supply blood and oxygen to the heart muscle. The lack of oxygen causing some local changes results in myocardial ischemia presented with chest pain, myocardial infarction (MI) when a coronary artery is blocked totally and may perhaps lead to death. However CHD seems to be an obstructive disease of the main coronary vessels and the routine practice of treatment is generally based on this definition. There are some other factors influencing the clinical results like endothelial dysfunction in microvascular bed that is also linked to atherosclerosis but with no obstruction. Vasospastic angina, a hyper-contraction of smooth muscle of a coronary artery without plaque formation may lead to MI or sudden death (33). The researches on syndrome X, microvascular angiopathy and slow coronary flow indicate that CHD symptoms may appear and stress-induced ischemia may be shown in some patients whose all major coronary vessels are proved completely open (34,35,36). Such patients with severe endothelial dysfunction in the absence of obstructive CHD have also been shown to have increased cardiac events (37). Slow coronary flow is a good example indicating the importance of function more than structure, so that, contrast agent in invasive coronary angiography (ICA) moves forward

slowly in some patients with angina pectoris when compared to normal individuals, although the patients have evidently normal coronary anatomy (38). On the other hand, clinical importance of obstructive CHD is not predictable according to the degree of narrowing, because there is no direct relationship between the degree of stenosis and cardiac events (39). Some compensating mechanisms occur in low and high-degree of stenosis. In early atherosclerosis with less than 50% stenosis in the vessels, plaque development and intimal thickening increase the total vessel area (expansive remodeling) to maintain lumen size 7.5%

4.5% 4%

23%

62%

Inpatient Care €14.2 billion Medications € 5.4 billion Primary Care € 1.5 billion Outpatient Care € 0.9 billion Accident & Emergency € 0.8 billion Formed with the data from Ref. 25

Figure 6. Direct health care cost for CHD in EU (€ 23 billion a year)

Table 3. Medical risk factors related to CHD in some European countries Prevalence of Hypertension, 2006 (%)

Estimated mean total cholesterol levels, aged 15+, 2010 (mmol/l) MEN WOMEN

Estimated prevalence of obesity, adults aged 15+, 2010, (%) MEN WOMEN

Estimated prevalence of diabetes, aged 20-79, 2010 (%)

Germany

37

5.6 5.6

22.9 26.3

12.0

UK Finland France Spain Greece

31 45 36 34 50

5.0 5.2 5.3 5.0 4.7

5.0 5.1 5.2 5.1 4.6

23.7 21.3 20.9 19.4 9.0 7.6 17.3 17.3 30.3 26.4

4.9 8.3 9.4 8.7 8.8

Estonia Hungary Latvia Lithuania Romania Turkey Bulgaria EU European Region

42 45 24 40 56 32* 63 36

5.0 5.4 5.3 5.3 5.1 4.5 5.7

5.2 5.1 5.3 5.4 5.0 4.6 5.9

8.6 8.4 15.8 16.1 9.7 15.0 16.8 13.9 5.5 12.0 10.8 32.5 17.0 19.0

9.9 8.8 9.9 9.7 8.4 7.4 9.0

Data from International Diabetes Federation (30).

Source

8.5 Data from European Commission ’s report (27)

Data from WHO Global Infobase Online (29).

Data from WHO Global Infobase Online (29).

*2003, Data from the study (PatenT) by B. Altun et al. (28).

Values are age-standardized to WHO Standard Population

Values are age-standardized to WHO Standard Population (Obese defined as BMI ≥ 30kg/m2 )

79

Taşçı et al. An Overview on Coronary Heart Disease

revascularization therapies targeting severe stenotic plaques do not help prevent the cardiac events when there are vulnerable plaques at the same time (46,47). Furthermore, some studies (CASS, ACME, AVERT, RITA-2, COURAGE and BARI 2D) comparing medical and surgical treatment strongly emphasize that coronary revascularization beyond optimal medical therapy may offer no substantial prognostic improvement in stable patients (48) (Table 6). All these conclusions indicate that CHD is not a simple disease of narrowed coronary arteries. Treatment Strategies Treatment strategies in managing stable CHD patients are controversial and still discussed in several studies (49,50,51,52,53,54,55,56,57,58,59,60,61,62,63,64,65,

and blood flow (40). Expansive remodeling despite its role to prevent ischemia is linked to plaque vulnerability and acute coronary syndromes (ACSs) like unstable angina, MI or sudden death. Over time, this positive remodeling becomes insufficient and is replaced with constrictive (or negative) remodeling. Constrictive remodeling is associated with much severe stenosis limiting blood flow and results in ischemia and stable angina presenting a relatively stable situation despite more progression in atherosclerotic pathway (40). Unfortunately, vulnerable plaques are generally asymptomatic, non-obstructive lesions that may rupture abruptly; therefore they are responsible for over 50% of cases of sudden death and acute MI (41). The content of vulnerable plaques is the reason for their unstable character. They are the soft plaques covered by a thin fibrous cap and include a large lipid core within a large amount of cholesterol esters and abundant macrophages indicating active inflammation. Severe stenotic plaques (narrowing >80% of the lumen) are more fibrotic and stable which are covered by a thick fibrous cap including less lipid core and macrophages, but more vessel smooth cells, collagen fibers and calcification (42). Both plaques usually exist together in a patient, and any imaging method even ICA, a gold standard in defining the degree of obstruction, tells us very little about which plaque may be responsible of future cardiac events (43,44). Finally in late atherosclerosis, chronic ischemia triggers new blood vessel growth to restore blood flow and oxygen supply to the affected areas like rendering a non-surgical natural by-pass (45). Because MI frequently develops from previously non-severe (10%), uncontrolled or worsening angina despite optimal medical therapy, impaired left ventricle (LV) function, significant proximal left anterior descending (LAD) or left main coronary artery (LMCA) stenosis (≥50%) and extensive multivessel disease. As the most important result pointing out function more than anatomy, revascularization with PCI or CABG has no significant additional effect on mortality and Table 5. Economic burden of CHD in some European countries (GNIpc) 2009 (PPP$)

Total health expenditure as % of GDP, 2008 (%) (PPP$)

Total health expenditure per capita, 2008

Cost per capita for CHD, 2003 (PPP€)

% cost of CHD of total health expenditure, 2003 (%)

Germany UK Finland France Spain Greece

36.850 35.860 35.280 33.950 31.490 28.800

10.4 9.0 8.4 11.1 8.7 9.7

3.692 3.230 2.979 3.778 2.791 2.852

75 82 49 32 26 40

3,0 4.1 2.8 1.4 1.7 2.4

Estonia Hungary Latvia Lithuania Romania Turkey Bulgaria EU European Region

19.120 19.090 17.610 17.310 14.540 13.500 13.260

5.9 7.4 6.5 6.2 4.7 5.0 7.3

1.226 1.419 1.112 1.178 665 695 910

20 20 17 25 50

3.1 2.0 3.7 4.4 2.6

7.6

1.969

Data from The World Bank, Last Updated on April 21, 2011 (31,32).

Data from WHO/Europe database (26).

Data from WHO/Europe database (26).

Data from the study by J. Leal et al. (25).

Data from the study by J. Leal et al. (25).

GNIpc: Gross National Income per capita

GDP: Gross Domestic Product

PPP$: Purchasing Power Parity Dollars

PPP€: Purchasing Power Parity Euros

Source

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Taşçı et al. An Overview on Coronary Heart Disease

anymore). New hybrid devices and new multimodality noninvasive imaging techniques searching different features of the disease in different stages are announced each year, and these developments bring new discussions on management of CHD (75). Noninvasive testing in stable CHD patients is still one of the most argued issues in medicine, although the clinical management of patients is carefully outlined in the “Guidelines of American College of Cardiology (ACC)/American Heart Association (AHA)/American College of Physicians/ASIM for the Management of Patients with Chronic Stable Angina”, that was first published in 1999, and updated in 2002, and “Guidelines on the management of stable angina pectoris” of European Society of Cardiology (ESC), in 2006” (76,77). These guidelines tabulate the multiple published data on diagnostic use of the tests, emphasize the evidence levels, appropriateness criteria or contraindications and establish some flow diagrams about initial clinical assessment, diagnosis and treatment. These guidelines particularly ACC/AHA guidelines designate the noninvasive tests (stress ECG, stress MPS, stress echocardiography) in a concept of “stress testing with or without imaging”. Both guidelines place ICA as an invasive test at the end of the diagnostic flow diagram to be reserved particularly for the high risk patients who have severe or uncontrolled angina or an evidence of ischemia in the absence of disabling

100.000 1800

1606 DALYs rates

1332 1344 1137 1176

Mortality rales

1600 1400 1200 574

1000 800

symptoms. So, the major purpose of the use of “stress testing with or without imaging” is to indicate an objective evidence of ischemia. Because ischemia means risk in CHD patients, these tests are valuable not only for demonstrating the disease, but also for risk stratification that has long been recognized as critical in the clinical management of stable patients. “Stress testing with or without imaging” can distinguish high-risk patients who may benefit from early ICA, from non-high risk patients in whom optimal medical therapy is enough to control the disease. The patients at intermediate pretest risk are supposed to get maximum benefit from a noninvasive test, because the test makes a real change in posttest probability in this group of patients. Relatively fewer ones are supposed to be seperated as at high risk after noninvasive testing who need further investigation and/or revascularization that are costly. The annual cardiac event rate in patients who are found to be at low risk by “stress testing with or without imaging” is less than 1% (which is similar for low risk Duke treadmill scores and normal studies of stress MPS or stress echocardiography) (78). So, the non-high risk patients will only be investigated further if their symptoms cannot be controlled with medical therapy alone. That’s why ischemia searching strategy provides better prognostic outcomes with less expenditure while stenosis searching strategy causes unnecessary revascularization without any improvement in prognosis. Another potential advantage of noninvasive stress testing is the demonstration of ischemia in patients without obstructive CHD who do not need revascularization, although they have relatively poor prognosis (78). In the routine practice, clinical presentation, severity of angina, pretest probability, expected clinical utility, economic availability, contraindications and patient preferences are considered for choosing the optimal diagnostic test or strategy. Hovewer, the appropriate use of the tests are established in the guidelines basically according to the existence of the symptoms and pretest probability. Diagnostic strategies for ACSs are beyond the scope of this article, and only the guidelines about symptomatic stable patients and asymptomatic adults considering “stress testing with or without imaging” will be mentioned here shortly. In asymptomatic adults (79), global risk scoring (such as the Framingham risk scoring) is recommended for cardiovascular risk assesment, but exercise ECG (that may only be considered

259 657

1449

687

259 368

600 400 200

Hu ng ary Ro ma nia Tu rke Bu y lga ri Lit a hu an ia Es to nia La tvi a

Uk Fin lan d

Fra nc e Sp ain Ge rm an y Gr ee ce

0

Data from the sources mentioned in Table 2

Cardiac Death Rate

13260

14540

15000 10000

8%

4.8% 3.7%

4%

3.3%

2.9%

2.0%

1.8% 2%

0.7%

0

0%

7110 16

Es to nia Hu ng ary La tv Lu ia th Ro unia ma n Tu ia rke y Bu lga ria

6.7%

6.3%

6%

5000

Ge rm an y UK Fin lan d Fra nc e Sp ai Gr n ee ce

Revasc Rx

10% 13500

20000

17610

25000

17310

Medical Rx 19120

30000

19090

33950

(GNIpc (PPP$) 28800

35000

31490

35280

36850

(PPP$) 40000

35860

Figure 8. Age-standardized DALYs rates and mortality rates in some European countries

1.0% 1331 56 1-5%

718 109 56 5-10%

545 234 11-20%

252 267 >20%

% Total Myocardium Ischemic

Data from the World Bank, Last Updated in April 2011 (26,27)

Figure 10. Observed cardiac death rates over the follow-up period in patients undergoing revascularization (Revasc Rx) vs medical therapy (Medical Rx) as a function of the amount of inducible ischemia. (P